PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our NIH-supported research program encompasses synthetic, mechanistic, and structural organic chemis- try. We address unresolved contemporary problems through studies that lead to i) new ways to make mole- cules, ii) new molecules with promise of valuable biological properties, iii) new insights about how chemical re- actions, including spontaneous biosynthetic transformations, proceed, and iv) new ways of deducing the struc- tures of novel chemical entities, often through innovative use of nuclear magnetic resonance (NMR) methodol- ogies. We plan to capitalize on recent accomplishments in two topical areas, I. and II. I. Natural Products Chemistry Three subtopics are pursued. A. We frequently engage in natural product structure determination studies. These challenges have often required that we develop new NMR strategies for interrogating complex structures. These studies have had im- pact extending far beyond the specific question being addressed. Our track record is strong. Our most notable recent example teaches methodology for calculation of chemical shifts to the experimentalist who may be a nov- ice computationalist. Earlier contributions include first-order multiplet analysis and ?No-D? NMR spectroscopy. B. We plan to capitalize on our previous work in the synthesis of extremely potent cytotoxins. If their acute cytotoxicity could be properly harnessed, these agents have the potential to be quite useful as chemo- therapeutic agents in oncology. We have the opportunity to do just that through collaborative studies using: (i) nanoparticle formulations targeted for portions of tumors called cancer stem cells or (ii) novel antibody-drug conjugates that also have the potential to improve the therapeutic window of these powerful agents. C. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis?that is, spontaneously. Specific hypotheses driving future work involve (i) an unprecedented Cope rearrangement to fashion the unique skeleton of ottelione A from an achiral diarylhep- tanoid and (ii) an isomerization of a highly unsaturated linear precursor (a tetrayne) to the bicyclic hydrocarbon core skeleton of the 9-membered enediyne family of natural products; a cyclase for this event remains elusive. II. HDDA*-Benzyne Chemistry (*hexadehydro-Diels-Alder). Our discovery of the broad scope of the hexadehydro-Diels?Alder (HDDA) reaction is both exciting and en- abling. This work blossomed tremendously during the current funding period of our NIGMS grant. Many of the reaction classes that we have A. Recently Published or that are the subject of B. Ongoing/Future Research are revolutionary. In a number of instances, these thermally induced, uncatalyzed transformations are not just remarkable, but were, literally, inconceivable prior to this work. The opportunities in this program show no sign of abating. To the contrary, it seems that every week or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of ?Wow, they'll also do that!? (30 lines)